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PLoS Genetics

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https://www.readbyqxmd.com/read/29782499/tgf%C3%AE-signaling-limits-lineage-plasticity-in-prostate-cancer
#1
Yi Hao, Glen A Bjerke, Karolina Pietrzak, Tiffany A Melhuish, Yu Han, Stephen D Turner, Henry F Frierson, David Wotton
Although treatment options for localized prostate cancer (CaP) are initially effective, the five-year survival for metastatic CaP is below 30%. Mutation or deletion of the PTEN tumor suppressor is a frequent event in metastatic CaP, and inactivation of the transforming growth factor (TGF) ß signaling pathway is associated with more advanced disease. We previously demonstrated that mouse models of CaP based on inactivation of Pten and the TGFß type II receptor (Tgfbr2) rapidly become invasive and metastatic...
May 21, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29782489/systematic-identification-of-factors-mediating-accelerated-mrna-degradation-in-response-to-changes-in-environmental-nitrogen
#2
Darach Miller, Nathan Brandt, David Gresham
Cellular responses to changing environments frequently involve rapid reprogramming of the transcriptome. Regulated changes in mRNA degradation rates can accelerate reprogramming by clearing or stabilizing extant transcripts. Here, we measured mRNA stability using 4-thiouracil labeling in the budding yeast Saccharomyces cerevisiae during a nitrogen upshift and found that 78 mRNAs are subject to destabilization. These transcripts include Nitrogen Catabolite Repression (NCR) and carbon metabolism mRNAs, suggesting that mRNA destabilization is a mechanism for targeted reprogramming of the transcriptome...
May 21, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29782485/evaluation-and-application-of-summary-statistic-imputation-to-discover-new-height-associated-loci
#3
Sina Rüeger, Aaron McDaid, Zoltán Kutalik
As most of the heritability of complex traits is attributed to common and low frequency genetic variants, imputing them by combining genotyping chips and large sequenced reference panels is the most cost-effective approach to discover the genetic basis of these traits. Association summary statistics from genome-wide meta-analyses are available for hundreds of traits. Updating these to ever-increasing reference panels is very cumbersome as it requires reimputation of the genetic data, rerunning the association scan, and meta-analysing the results...
May 21, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29771908/elevated-temperature-increases-meiotic-crossover-frequency-via-the-interfering-type-i-pathway-in-arabidopsis-thaliana
#4
Jennifer L Modliszewski, Hongkuan Wang, Ashley R Albright, Scott M Lewis, Alexander R Bennett, Jiyue Huang, Hong Ma, Yingxiang Wang, Gregory P Copenhaver
For most eukaryotes, sexual reproduction is a fundamental process that requires meiosis. In turn, meiosis typically depends on a reciprocal exchange of DNA between each pair of homologous chromosomes, known as a crossover (CO), to ensure proper chromosome segregation. The frequency and distribution of COs are regulated by intrinsic and extrinsic environmental factors, but much more is known about the molecular mechanisms governing the former compared to the latter. Here we show that elevated temperature induces meiotic hyper-recombination in Arabidopsis thaliana and we use genetic analysis with mutants in different recombination pathways to demonstrate that the extra COs are derived from the major Type I interference sensitive pathway...
May 17, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29768408/a-homozygous-kat2b-variant-modulates-the-clinical-phenotype-of-add3-deficiency-in-humans-and-flies
#5
Sara Gonçalves, Julie Patat, Maria Clara Guida, Noelle Lachaussée, Christelle Arrondel, Martin Helmstädter, Olivia Boyer, Olivier Gribouval, Marie-Claire Gubler, Geraldine Mollet, Marlène Rio, Marina Charbit, Christine Bole-Feysot, Patrick Nitschke, Tobias B Huber, Patricia G Wheeler, Devon Haynes, Jane Juusola, Thierry Billette de Villemeur, Caroline Nava, Alexandra Afenjar, Boris Keren, Rolf Bodmer, Corinne Antignac, Matias Simons
Recent evidence suggests that the presence of more than one pathogenic mutation in a single patient is more common than previously anticipated. One of the challenges hereby is to dissect the contribution of each gene mutation, for which animal models such as Drosophila can provide a valuable aid. Here, we identified three families with mutations in ADD3, encoding for adducin-γ, with intellectual disability, microcephaly, cataracts and skeletal defects. In one of the families with additional cardiomyopathy and steroid-resistant nephrotic syndrome (SRNS), we found a homozygous variant in KAT2B, encoding the lysine acetyltransferase 2B, with impact on KAT2B protein levels in patient fibroblasts, suggesting that this second mutation might contribute to the increased disease spectrum...
May 16, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29768402/condensin-i-protects-meiotic-cohesin-from-wapl-1-mediated-removal
#6
Margarita R Hernandez, Michael B Davis, Jianhao Jiang, Elizabeth A Brouhard, Aaron F Severson, Györgyi Csankovszki
Condensin complexes are key determinants of higher-order chromatin structure and are required for mitotic and meiotic chromosome compaction and segregation. We identified a new role for condensin in the maintenance of sister chromatid cohesion during C. elegans meiosis. Using conventional and stimulated emission depletion (STED) microscopy we show that levels of chromosomally-bound cohesin were significantly reduced in dpy-28 mutants, which lack a subunit of condensin I. SYP-1, a component of the synaptonemal complex central region, was also diminished, but no decrease in the axial element protein HTP-3 was observed...
May 16, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29763432/distinctive-types-of-postzygotic-single-nucleotide-mosaicisms-in-healthy-individuals-revealed-by-genome-wide-profiling-of-multiple-organs
#7
August Yue Huang, Xiaoxu Yang, Sheng Wang, Xianing Zheng, Qixi Wu, Adam Yongxin Ye, Liping Wei
Postzygotic single-nucleotide mosaicisms (pSNMs) have been extensively studied in tumors and are known to play critical roles in tumorigenesis. However, the patterns and origin of pSNMs in normal organs of healthy humans remain largely unknown. Using whole-genome sequencing and ultra-deep amplicon re-sequencing, we identified and validated 164 pSNMs from 27 postmortem organ samples obtained from five healthy donors. The mutant allele fractions ranged from 1.0% to 29.7%. Inter- and intra-organ comparison revealed two distinctive types of pSNMs, with about half originating during early embryogenesis (embryonic pSNMs) and the remaining more likely to result from clonal expansion events that had occurred more recently (clonal expansion pSNMs)...
May 15, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29758044/prickle-is-phosphorylated-by-nemo-and-targeted-for-degradation-to-maintain-prickle-spiny-legs-isoform-balance-during-planar-cell-polarity-establishment
#8
Giovanna M Collu, Andreas Jenny, Konstantin Gaengel, Ivana Mirkovic, Mei-Ling Chin, Ursula Weber, Michael J Smith, Marek Mlodzik
Planar cell polarity (PCP) instructs tissue patterning in a wide range of organisms from fruit flies to humans. PCP signaling coordinates cell behavior across tissues and is integrated by cells to couple cell fate identity with position in a developing tissue. In the fly eye, PCP signaling is required for the specification of R3 and R4 photoreceptors based upon their positioning relative to the dorso-ventral axis. The 'core' PCP pathway involves the asymmetric localization of two distinct membrane-bound complexes, one containing Frizzled (Fz, required in R3) and the other Van Gogh (Vang, required in R4)...
May 14, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29758020/defining-icr-mo-an-intrinsic-colistin-resistance-determinant-from-moraxella-osloensis
#9
Wenhui Wei, Swaminath Srinivas, Jingxia Lin, Zichen Tang, Shihua Wang, Saif Ullah, Vishnu Goutham Kota, Youjun Feng
Polymyxin is the last line of defense against severe infections caused by carbapenem-resistant gram-negative pathogens. The emergence of transferable MCR-1/2 polymyxin resistance greatly challenges the renewed interest in colistin (polymyxin E) for clinical treatments. Recent studies have suggested that Moraxella species are a putative reservoir for MCR-1/2 genetic determinants. Here, we report the functional definition of ICR-Mo from M. osloensis, a chromosomally encoded determinant of colistin resistance, in close relation to current MCR-1/2 family...
May 14, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29750810/mtor-signaling-regulates-central-and-peripheral-circadian-clock-function
#10
Chidambaram Ramanathan, Nimish D Kathale, Dong Liu, Choogon Lee, David A Freeman, John B Hogenesch, Ruifeng Cao, Andrew C Liu
The circadian clock coordinates physiology and metabolism. mTOR (mammalian/mechanistic target of rapamycin) is a major intracellular sensor that integrates nutrient and energy status to regulate protein synthesis, metabolism, and cell growth. Previous studies have identified a key role for mTOR in regulating photic entrainment and synchrony of the central circadian clock in the suprachiasmatic nucleus (SCN). Given that mTOR activities exhibit robust circadian oscillations in a variety of tissues and cells including the SCN, here we continued to investigate the role of mTOR in orchestrating autonomous clock functions in central and peripheral circadian oscillators...
May 11, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29750799/population-specific-genetic-modification-of-huntington-s-disease-in-venezuela
#11
Michael J Chao, Kyung-Hee Kim, Jun Wan Shin, Diane Lucente, Vanessa C Wheeler, Hong Li, Jared C Roach, Leroy Hood, Nancy S Wexler, Laura B Jardim, Peter Holmans, Lesley Jones, Michael Orth, Seung Kwak, Marcy E MacDonald, James F Gusella, Jong-Min Lee
Modifiers of Mendelian disorders can provide insights into disease mechanisms and guide therapeutic strategies. A recent genome-wide association (GWA) study discovered genetic modifiers of Huntington's disease (HD) onset in Europeans. Here, we performed whole genome sequencing and GWA analysis of a Venezuelan HD cluster whose families were crucial for the original mapping of the HD gene defect. The Venezuelan HD subjects develop motor symptoms earlier than their European counterparts, implying the potential for population-specific modifiers...
May 11, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29746474/analysis-of-motor-dysfunction-in-down-syndrome-reveals-motor-neuron-degeneration
#12
Sheona Watson-Scales, Bernadett Kalmar, Eva Lana-Elola, Dorota Gibbins, Federica La Russa, Frances Wiseman, Matthew Williamson, Rachele Saccon, Amy Slender, Anna Olerinyova, Radma Mahmood, Emma Nye, Heather Cater, Sara Wells, Y Eugene Yu, David L H Bennett, Linda Greensmith, Elizabeth M C Fisher, Victor L J Tybulewicz
Down Syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and results in a spectrum of phenotypes including learning and memory deficits, and motor dysfunction. It has been hypothesized that an additional copy of a few Hsa21 dosage-sensitive genes causes these phenotypes, but this has been challenged by observations that aneuploidy can cause phenotypes by the mass action of large numbers of genes, with undetectable contributions from individual sequences. The motor abnormalities in DS are relatively understudied-the identity of causative dosage-sensitive genes and the mechanism underpinning the phenotypes are unknown...
May 10, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29742103/shoc1-is-a-ercc4-hhh-2-like-protein-integral-to-the-formation-of-crossover-recombination-intermediates-during-mammalian-meiosis
#13
Michel F Guiraldelli, Anna Felberg, Luciana P Almeida, Aniruddha Parikh, Rodrigo O de Castro, Roberto J Pezza
Chromosome segregation errors during meiosis result in the formation of aneuploid gametes and are the leading cause of pregnancy loss and birth defects in humans. Proper chromosome segregation requires pairwise associations of maternal and paternal homologous chromosomes. Chiasmata, which are the cytological manifestations of crossovers (COs), provide a physical link that holds the homologs together as a pair, facilitating their orientation on the spindle at meiosis I. Although CO-promoting activities ensure a balanced number and position of COs, their identity and mechanism of action in mammals remain understudied...
May 9, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29738522/de-novo-and-inherited-private-variants-in-map1b-in-periventricular-nodular-heterotopia
#14
Erin L Heinzen, Adam C O'Neill, Xiaolin Zhu, Andrew S Allen, Melanie Bahlo, Jamel Chelly, William B Dobyns, Saskia Freytag, Renzo Guerrini, Richard J Leventer, Annapurna Poduri, Stephen P Robertson, Christopher A Walsh, Mengqi Zhang
Periventricular nodular heterotopia (PVNH) is a malformation of cortical development commonly associated with epilepsy. We exome sequenced 202 individuals with sporadic PVNH to identify novel genetic risk loci. We first performed a trio-based analysis and identified 219 de novo variants. Although no novel genes were implicated in this initial analysis, PVNH cases were found overall to have a significant excess of nonsynonymous de novo variants in intolerant genes (p = 3.27x10-7), suggesting a role for rare new alleles in genes yet to be associated with the condition...
May 8, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29734336/dynamics-and-control-of-sister-kinetochore-behavior-during-the-meiotic-divisions-in-drosophila-spermatocytes
#15
Soumya Chaurasia, Christian F Lehner
Sister kinetochores are connected to the same spindle pole during meiosis I and to opposite poles during meiosis II. The molecular mechanisms controlling the distinct behavior of sister kinetochores during the two meiotic divisions are poorly understood. To study kinetochore behavior during meiosis, we have optimized time lapse imaging with Drosophila spermatocytes, enabling kinetochore tracking with high temporal and spatial resolution through both meiotic divisions. The correct bipolar orientation of chromosomes within the spindle proceeds rapidly during both divisions...
May 7, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29734333/a-coupled-process-of-same-and-opposite-sex-mating-generates-polyploidy-and-genetic-diversity-in-candida-tropicalis
#16
Han Du, Qiushi Zheng, Jian Bing, Richard J Bennett, Guanghua Huang
Sexual reproduction is a universal mechanism for generating genetic diversity in eukaryotes. Fungi exhibit diverse strategies for sexual reproduction both in nature and in the laboratory. In this study, we report the discovery of same-sex (homothallic) mating in the human fungal pathogen Candida tropicalis. We show that same-sex mating occurs between two cells carrying the same mating type (MTLa/a or α/α) and requires the presence of pheromone from the opposite mating type as well as the receptor for this pheromone...
May 7, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29734330/sustained-activation-of-detoxification-pathways-promotes-liver-carcinogenesis-in-response-to-chronic-bile-acid-mediated-damage
#17
Agnese Collino, Alberto Termanini, Paola Nicoli, Giuseppe Diaferia, Sara Polletti, Camilla Recordati, Vittoria Castiglioni, Donatella Caruso, Nico Mitro, Gioacchino Natoli, Serena Ghisletti
Chronic inflammation promotes oncogenic transformation and tumor progression. Many inflammatory agents also generate a toxic microenvironment, implying that adaptive mechanisms must be deployed for cells to survive and undergo transformation in such unfavorable contexts. A paradigmatic case is represented by cancers occurring in pediatric patients with genetic defects of hepatocyte phosphatidylcholine transporters and in the corresponding mouse model (Mdr2-/- mice), in which impaired bile salt emulsification leads to chronic hepatocyte damage and inflammation, eventually resulting in oncogenic transformation...
May 7, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29727464/patterns-of-chromatin-accessibility-along-the-anterior-posterior-axis-in-the-early-drosophila-embryo
#18
Jenna E Haines, Michael B Eisen
As the Drosophila embryo transitions from the use of maternal RNAs to zygotic transcription, domains of open chromatin, with relatively low nucleosome density and specific histone marks, are established at promoters and enhancers involved in patterned embryonic transcription. However it remains unclear how regions of activity are established during early embryogenesis, and if they are the product of spatially restricted or ubiquitous processes. To shed light on this question, we probed chromatin accessibility across the anterior-posterior axis (A-P) of early Drosophila melanogaster embryos by applying a transposon based assay for chromatin accessibility (ATAC-seq) to anterior and posterior halves of hand-dissected, cellular blastoderm embryos...
May 4, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29723192/the-are-binding-protein-tristetraprolin-ttp-is-a-novel-target-and-mediator-of-calcineurin-tumor-suppressing-function-in-the-skin
#19
Xunwei Wu, Alice Tommasi di Vignano, Qian Zhou, Piotr J Michel-Dziunycz, Fuxiang Bai, Jun Mi, Jing Qin, Tingjian Zu, Günther F L Hofbauer
An increased incidence of skin inflammatory diseases is frequently observed in organtransplanted patients being treated with calcineurin inhibitor-based immunosuppressive agents. The mechanism of increased skin inflammation in this context has however not yet been clarified. Here we report an increased inflammation following inhibition of calcineurin signaling seen in both chemically induced mouse skin tumors and in tumors grafted from H-rasV12 expressing primary human keratinocytes (HKCs). Following UVB or TPA treatment, we specifically found that deletion of the calcineurin gene in mouse keratinocytes (MKCs) resulted in increased inflammation, and this was accompanied by the enhanced production of pro-inflammatory cytokines, such as TNFα, IL-8 and CXCL1...
May 3, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29723191/role-of-duplicate-genes-in-determining-the-tissue-selectivity-of-hereditary-diseases
#20
Ruth Barshir, Idan Hekselman, Netta Shemesh, Moran Sharon, Lena Novack, Esti Yeger-Lotem
A longstanding puzzle in human genetics is what limits the clinical manifestation of hundreds of hereditary diseases to certain tissues, while their causal genes are expressed throughout the human body. A general conception is that tissue-selective disease phenotypes emerge when masking factors operate in unaffected tissues, but are specifically absent or insufficient in disease-manifesting tissues. Although this conception has critical impact on the understanding of disease manifestation, it was never challenged in a systematic manner across a variety of hereditary diseases and affected tissues...
May 3, 2018: PLoS Genetics
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